The candidate, a granulocyte-macrophage colony stimulating factor (GM-CSF)-adjuvanted DNA/MVA vaccine being developed by GeoVax, recently received an “Allowed to Proceed” notice from the FDA for testing in humans.
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Opened in April, the Phase I trial, sponsored by NIAID and conducted by the HIV Vaccine Trials Network (HVTN), is testing the vaccine for safety and immunogenicity in participants who are at low risk of exposure to HIV. The sites for HVTN 094, as the trial protocol is named, include the San Francisco Department of Public Health, the University of Rochester, The Alabama Vaccine Center in Birmingham, and Brigham and Women’s Hospital in Boston. If all goes well for HVTN 094, its results may allow researchers to proceed directly to a “ramp-in” Phase IIb efficacy trial in individuals who are considered to be at high risk for HIV infection.

Building on the past
Lead investigator Harriet Robinson, PhD, Chief Scientific Officer at GeoVax, has been developing this vaccine technology, which has candidates in both the preventative and therapeutic categories. As a preventative vaccine, the DNA/MVA, prime/boost regimen seeks to elicit anti-HIV-1 T-cell and antibody responses. It does so by expressing the three major proteins of HIV in virus-like particles that look like HIV but are missing proteins necessary to replicate. The body reacts to what it thinks is HIV without the danger of infection. The goal is to achieve a vaccine that would protect against multiple exposures
to HIV.
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The prime/boost strategy works like this: The immune response is focused toward the HIV proteins expressed by the DNA vaccine and then, once primed, the MVA (modified vaccinia Ankara) live virus vector boosts the immune response by expressing larger amounts of protein than can be achieved by DNA alone and by the infection triggering proinflammatory responses that enhance immunity in the individual.
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In past Phase I and Phase IIa studies, the first generation of the GeoVax DNA/MVA vaccine, without GM-CSF, has shown excellent safety and reproducible vaccine responses in over 400 uninfected individuals.

Second generation vaccine
As an adjuvant in this second-generation vaccine candidate, granulocyte-macrophage colony stimulating factor (GM-CSF), a normal human protein, is co-expressed in the DNA but not the MVA component of the vaccine regimen. The DNA expresses the GM-CSF alongside the expression of the HIV proteins right at the site of vaccination. GM-CSF has the potential to increase vaccine efficacy by stimulating the initiation of immune responses. In particular, GM-CSF stimulates the expansion and differentiation of white blood cells (dendritic cells and macrophages) that initiate immune responses.
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As an adjuvant to therapies, GM-CSF has a track record in the treatment of other conditions. GM-CSF is licensed to stimulate production of white blood cells after autologous bone marrow transplantation, and is approved as a treatment for fungal infections as well as an adjuvant for Provenge, a prostate cancer vaccine. This history gives researchers and regulators more data with which to evaluate its safety in humans.
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“We did our first experiments with GM-CSF in 1998, 1999. What we found was that GM-CSF improved control of infection. We used to do single, high-dose exposures to virus to test how well a vaccine was working. With a single high dose we would infect all animals, but observe reductions in the peak levels of virus replication after the exposure,” says Dr. Robinson. After the researchers received needed grant money, they were able to study the model in more detail. “Instead of conducting a single high-dose exposure, we administered repeated moderate dose rectal exposures to the virus [for twelve successive weeks], where each exposure infected thirty percent of the animals in the unvaccinated group. There, the GM-CSF made a tremendous difference in prevention of infection. In the presence of the GM-CSF, we went from a sixty percent to a ninety percent per exposure reduction in risk of infection.”
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The addition of GM-CSF to the product has moved forward to human testing. “For us to put GM-CSF into our product meant that the timeline for the product had to be adjusted, but the GM-CSF effect is large and you really want to prevent HIV infections not just control virus levels. Controlling virus levels is good—that’s what drugs do and you can see the miracle that has happened with the use of drugs—but, if you get a vaccine that can prevent infection, that is big.”
Within a year, and in record time, GeoVax has overseen manufacture of the GM-CSF co-expressing DNA, compiled and filed the paperwork with the U.S. FDA to secure permission to proceed, and now the HIV Vaccine Trials Network has opened the trial.

Allowed to proceed
Dr. Robinson stresses testing candidate vaccines first in animal models before introducing them into humans. The objectives of the first human trial are safety and immunogenicity. “We don’t anticipate problems in safety because there are no indications that the levels of GM-CSF in this vaccine are unsafe in humans, and there’s been a lot of human experience with GM-CSF,” notes Dr. Robinson.
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“And we’ve had absolutely no indications of any safety issues in the non-human primate studies. In humans we need to see if the vaccine is still raising the same kinds of immune responses that we saw in the non-human primate model with the GM-CSF co-expressing vaccine. We anticipate that this will be so because in the non-human primate model we use simian immunodeficiency virus (SIV) vaccines co-expressing the macaque GM-CSF. We expect to see very similar phenomena in humans with the HIV vaccine co-expressing the human GM-CSF.”

Developing alternatives
In a 2009 interview with A&U, Dr. Robinson talked about GeoVax’s other preventative candidate, an MVA/MVA prime boost vaccine. GeoVax is also working on therapeutic versions of this vaccine technology, without co-expressed GM-CSF. “We’ve really made progess [since 2009 when we last talked]. With the preventative vaccine, we actually have the hope of preventing infection—that’s really good. The therapeutic vaccine trial has been slow to enroll because of the enrollment criteria—participants need to have documentation of their approximate date of infection and to have started drugs within eighteen months of seroconversion, but we’re moving, we’re moving along.”

Dr. Robinson says that her team has submitted a grant for the MVA/MVA, prime/boost as a preventative vaccine candidate, but, at this juncture, they are focused on moving forward with the more effective GM-CSF DNA prime and MVA boost for the developed world.

However, “the MVA priming and boosting would be particularly valuable for the developing world, where to have a single regimen and a lower cost of a single-component regimen would be important.”

Prevention + prevention
“In the non-human primates, prevention is at a ninety percent reduction in per exposure risk, but we do not know what the efficacy will be in people and trial participants are going to be encouraged to take every safety procedure they can,” says Dr. Robinson about future trials. “The trial sizes are being planned to be large enough that people could be taking pre-exposure prophylaxis drugs.” If and when this vaccine technology comes to fruition, a preventative vaccine would most likely be used in conjunction with other prevention tools, like condoms. Says Dr. Robinson: “Until we have extensive human experience, vaccinated people should continue to use safe [sex] practices.”